While the primary focus for the development of rejuvenation therapies to address the contribution of senescent cells to the aging process is to destroy these harmful, errant cells, many research groups are more interested in modulating or suppressing the senescence-associated secretory phenotype (SASP). The SASP is a potent mix of inflammatory and other signals that disrupts tissue function and produces a sizable fraction of the chronic inflammation associated with aging, driving the progression of all of the common age-related conditions. In principle, eliminating the SASP should eliminate the contribution of senescent cells to the aging process; the challenge would be doing so without also eliminating the necessary short-term SASP involved in cancer suppression, wound healing, and other positive functions carried out by senescent cells on a temporary basis. Periodic destruction of lingering senescent cells doesn't have this hurdle to clear, as it won't interfere with the short-term presence of senescent cells that come and go as needed.
Cellular senescence is an important protective process with roles in development, tissue homeostasis, and wound healing. However, senescence is also implicated in multiple diseases including cancer, arthritis, atherosclerosis, and a diminished healthspan during aging. The senescence-associated secretory phenotype (SASP) is an important hallmark of senescence that contributes to normal physiology and disease. The SASP is characterised by the release of inflammatory cytokines, chemokines, growth factors, and proteases. This reinforces senescence through autocrine and paracrine signalling, and recruits and instructs immune cells to clear senescent cells. However, senescent cells can also generate an inflammatory environment. Thus, the SASP is often considered a double-edge sword. Whilst promoting immune-mediated clearance of pre-malignant senescent cells is a powerful barrier against transformation, the SASP from uncleared senescent cells, or those arising during natural aging, can create an inflammatory milieu permissive to disease.
The SASP is regulated by interleukin-1 alpha (IL-1α), but the mechanism of IL-1α activation during senescence is unknown. Previous studies have suggested that NLRP3 inflammasomes modulate the SASP, even though caspase-1 cannot activate IL-1α. However, our recent research has demonstrated that caspase-5, which lies upstream of NLRP3 in the non-canonical inflammasome pathway, induces IL-1α activity and regulates the SASP during oncogene-induced senescence (OIS) in vitro and in vivo. Recent research also implicates the non-canonical inflammasome in sterile inflammation, of which the SASP is an important yet rarely cited example.
Our recent investigation demonstrated that caspase-5 or caspase-11, but not caspase-4 or caspase-1, specifically cleaves human or mouse pro-IL-1α at a highly conserved site. We demonstrated that caspase-5/11 is required for IL-1α release from cells. siRNA-mediated caspase-5 knockdown reduced levels of cell-surface and secreted IL-1α, and impaired release of the common SASP factors IL-6, IL-8, and MCP-1 from senescent fibroblasts. Our work identifying caspase-5 as a novel regulator of IL-1α activity and the SASP raises several important questions for future research. Firstly, it will be important to understand how caspase-5 is activated in senescent cells. We demonstrated that knockdown of CGAS results in reduced caspase-5 expression and an impaired SASP, and hypothesised that cGAS/STING activated by cytosolic chromatin in senescent cells may drive caspase-5 expression via type I interferons.
The discovery of caspase-5 as a novel regulator of IL-1α in sterile and non-sterile inflammation has several important clinical implications. Targeting caspase-5 may be a therapeutic strategy that leaves canonical immune responses via caspase-1 and -4 intact. For instance, radiotherapy and chemotherapy induce DNA damage that can trigger tumour cell senescence. However, these non-selective therapies also induce senescence in the underlying stroma, with IL-6 from senescent fibroblasts shown to be a reprogramming factor that drives pluripotency and proliferation of cancer stem cells surviving treatment. Therefore, caspase-5 inhibition during treatment could lessen the chance of tumour recurrence.